Clozapine but not haloperidol antagonizes an MK-801 discriminative stimulus cue.

The noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) produced an interoceptive stimulus cue in rats trained to discriminate between MK-801 (0.075 mg/kg) and saline in a two-choice, discrete trial avoidance paradigm. Haloperidol (0.03-0.3 mg/kg) failed to antagonize the discriminative stimulus cue of MK-801, with all rats choosing the MK-801-appropriate choice lever. Higher doses of haloperidol (1.0 mg/kg) produced significant sedation such that the rats were unable to complete all the trials. In contrast, clozapine dose dependently antagoinzed the discriminative stimulus cue produced by MK-801. Clozapine at a dose of 3.0 mg/kg completely antagonized the stimulus cue produced by MK-801. Therefore, the discriminative stimulus cue produced by the noncompetitive NMDA antagonist MK-801 may be useful as an animal model for selecting novel drugs with potential efficacy for treatment-resistant schizophrenia.